Peroxisome proliferators which proliferate an intracellular granule, peroxisome, are thought as important controlling elements of lipid metabolism. A nuclear receptor, PPAR, which is activated by the peroxisome proliferator has turned out to be a multifunctional receptor concerning incretion, metabolism, inflammation or the like. Therefore, the ligand is thought to be able to apply as various medicines and the number of researches is recently increasing.
The subtype genes of PPARs are found from various animal organs and formed a family. In mammals, PPARs are classified into three subtypes of PPARα, PPARδ (also referred to as PPARβ) and PPARγ.
The drugs of the fibrate group used as an antihyperlipemic drug are thought to show the activity by PPARα activation-mediated transcriptional enhancement of the gene group which improves serum lipid. Additionally, it is suggested that PPARα may relate to bone metabolism and expression of the activity of non-steroidal anti-inflammatory drugs.
The thiazolidindion compounds, which are improving drugs for insulin resistance, are ligands of PPARγ. As these compounds show hypoglycemic action, hypolipidemic action, adipocyte differentiation-inducing action or the like, PPARγ agonists are expected to develop as therapeutic agents for diabetes, hyperlipidemia, obesity or the like. Furthermore, PPARγ agonists are expected to be therapeutic agents for chronic pancreatitis, inflammatory colitis, glomerulosclerosis, Alzheimer's disease, psoriasis, parkinsonism, Basedow's disease, chronic rheumatoid arthritis, cancer (breast cancer, colonic cancer, prostatic cancer or the like), sterility or the like.
It was reported that transgenic mice in which PPARδ is overexpressed specifically in adipocyte were difficult to get fat or the like. Therefore, PPARδ agonists can be used as an antiobestic drug or an antidiabetic drug. Additionally, PPARδ agonists are suggested the possibility as therapeutic agents for colonic cancer, osteoporosis, sterility, psoriasis, multiple sclerosis or the like.
Based on these findings, PPAR agonists are expected to be useful for treatment or prevention of hyperlipidemia, diabetes, hyperglycosemia, insulin resistance, obesity, arteriosclerosis, atherosclerosis, hypertension, syndrome X, inflammation, allergic disease (inflammatory colitis, chronic rheumatoid arthritis, chronic pancreatitis, multiple sclerosis, glomerulosclerosis, psoriasis or the like), osteoporosis, sterility, cancer, Alzheimer's disease, parkinsonism, Basedow's disease or the like (Non-Patent Document 1).
Patent Document 1 and Patent Document 2 disclosed various compounds having PPAR agonistic activity, for example, isoxazole compounds. However, compounds of the present invention were not disclosed. Furthermore, isoxazole compounds in Patent Document 2 have substituents on isoxazole in the different position compared to compounds of the present invention. Additionally, although PPARα and (or) PPARγ agonistic activity of the compounds were recognized, no data of PPARδ agonistic activity was disclosed. Furthermore, there was no data of isoxazole compounds even about PPARα or γ agonistic activity. In a word, the PPAR agonistic activity was not recognized.
Although Patent Document 3 disclosed isoxazole compounds, the compounds have substituents on isoxazole in the different position compared to compounds of the present invention. Furthermore, it was disclosed that the compounds are useful for hypercholesterolemia or hyperlipidemia. However, the PPAR agonistic activity was not disclosed.
Although Patent Document 4, 5 and 6 disclosed thiazole, oxazole and pyrazole compounds with PPARδ agonistic activity. However, isoxazole compounds were not suggested.
Patent Document 7, 8 and 9 disclosed isoxazole compounds. However, compounds of this invention were not disclosed.    [Patent Document 1] WO 99/11255    [Patent Document 2] WO 99/58510    [Patent Document 3] EP 0558062    [Patent Document 4] WO 01/00603    [Patent Document 5] WO 99/46232    [Patent Document 6] WO 04/063166    [Patent Document 7] WO 02/053547    [Patent Document 8] WO 03/099793    [Patent Document 9] WO 04/091604    [Non-patent Document 1]    Current Medicinal Chemistry, 2003, Vol. 10, p.p. 267-280